Lymphocytes are the central mediators of cellular and humoral immunity, but they depend on dendritic and other reticuloendothelial cells during development and for the generation of acquired immunity. Lymphocyte function and interactions with dendritic cells are regulated through cell-surface molecules that mediate intercellular communication, generate transmembrane signals, and direct lymphocyte development and localization within tissues. Aberrant lymphocyte and dendritic cell functions contribute to immunodeficiencies, autoimmune conditions, age-related defects in immunity, and malignancies. The aim of these studies is to examine the function of CD83, a cell-surface receptor that we first identified as a member of the immunoglobulin superfamily predominantly expressed by dendritic cells in humans. Based on the remarkable phenotype of CD83-deficient (CD83-/-) mice that we have generated, CD83 functions as an essential receptor for T lymphocyte selection and/or lineage commitment. Thus, CD83 engagement uniquely represents a new regulatory step for CD4+ T cell development in the thymus, but is likely to have additional functions in the immune system. We propose that CD83 expressed by mouse dendritic and thymic epithelial cells binds extracellular ligand(s), which inform developing and mature lymphocytes of their extracellular microenvironment in vivo. These signals may regulate lymphocyte activation and survival in the periphery and thereby regulate cellular and humoral immune responses. Three specific aims are designed to test this hypothesis and to further our knowledge of how CD83 regulates normal lymphocyte development and function. Specific aim 1 will determine how CD83 regulates thymocyte development in vivo and in vitro. Specific aim 2 will determine whether and how CD83 regulates peripheral lymphocyte survival. In specific aim 3, we will determine whether CD83 binding to extracellular ligand(s) regulates lymphocyte development and function in vivo by identifying and characterizing CD83 ligands expressed by mouse thymocytes. Since CD83 expression provides an important regulatory checkpoint for helper T cell development, understanding its function may provide mechanisms for modulating humoral immunity and for the treatment of immunodeficiency, autoimmunity and malignancies